(2R)-2-amino-3-methylbutanamide

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of D-valinamide (1.76 g, 14.7 mmol) in acetonitrile (30 mL) was slowly added 1,3-propanesultone (1.75 g, 14.4 mmol). The solution was stirred at reflux for 2 hours. The reaction mixture was cooled to room temperature. The solid was collected by filtration, washed with acetonitrile (2×25 mL). The solid product was dissolved in water (75 mL). Dowex Marathon C resin (strongly acidic) was added to the solution. The suspension was stirred for 15 minutes before the resin was removed by filtration. The filtrate was evaporated under reduced pressure. The solid material was suspended in acetone (50 mL), filtered and dried in vacuo, affording the title compound (1.57 g, 51%). 1H NMR (D2O, 500 MHz) δ ppm 3.80 (m, 1H), 3.19 (m, 2H), 3.00 (m, 2H), 2.25 (m, 1H), 2.16 (m, 2H), 1.08 (d, 3H, J=6.8 Hz), 1.02 (d, 3H, J=6.8 Hz). 13C (D2O, 125 MHz) δ ppm 169.94, 65.86, 48.10, 46.27, 29.54, 21.23, 17.99, 17.02. [α]D=−12.4° (c=0.0037 in water), ES-MS 237 (M−1). at reflux for 2 hours The solid was collected by filtration washed with acetonitrile (2×25 mL) The solid product was dissolved in water (75 mL) Dowex Marathon C resin (strongly acidic) was added to the solution The suspension was stirred for 15 minutes before the resin was removed by filtration The filtrate was evaporated under reduced pressure filtered dried in vacuo

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of (R)-2-amino-3-methyl-butyramide (50 mg), 2,4,5-trichloropyrimidine (67 mg) and K2CO3 (116 mg) in DMF (3 mL) was stirred at room temperature for 5 hr. The reaction mixture was diluted with DCM and washed with brine three times. The organic layer was dried with sodium sulfate and concentrated. The residue was purified by silica gel chromatography to provide 60 mg of (R)-2-(2,5-dichloro-pyrimidin-4-ylamino)-3-methyl-butyramide: 1H NMR (300 MHz, CDCl3) 8.2 (s, 1H), 6.2 (bs, 1H), 5.8 (bs, 1H), 5.6 (bs, 1H), 4.6 (dd, 1H), 2.4 (m, 1H), 1.2 (d, 6H). MS (m/e) 263 (M+1). washed with brine three times The organic layer was dried with sodium sulfate concentrated The residue was purified by silica gel chromatography

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of (R)-2-amino-3-methyl-butyramide (50 mg), 2,4,5-trichloropyrimidine (67 mg) and K2CO3 (116 mg) in DMF (3 mL) was stirred at room temperature for 5 hr. The reaction mixture was diluted with DCM and washed with brine three times. The organic layer was dried with sodium sulfate and concentrated. The residue was purified by silica gel chromatography to provide 60 mg of (R)-2-(2,5-dichloro-pyrimidin-4-ylamino)-3-methyl-butyramide: 1H NMR (300 MHz, CDCl3) 8.2 (s, 1H), 6.2 (bs, 1H), 5.8 (bs, 1H), 5.6 (bs, 1H), 4.6 (dd, 1H), 2.4 (m, 1H), 1.2 (d, 6H). MS (m/e) 263 (M+1). washed with brine three times The organic layer was dried with sodium sulfate concentrated The residue was purified by silica gel chromatography

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The title compound was prepared in a similar procedure as described in Example (R)-3-((1-amino-3-methyl-1-oxobutan-2-yl)amino)-5-((1-methyl-1H-indol-4-yl)amino)-1,2,4-triazine-6-carboxamide. Here though, 1H-Pyrazole-3-methanamine was utilized instead of (R)-2-amino-3-methylbutanamide. MS found for C17H17N9O as (M+H)+ 364.4. UV: λ=211, 239 nm. Proton NMR: (CD3OD) δ 7.90 (1H, d, J=8.0 Hz), 7.62 (1H, m), 7.34 (1H, d, J=8.8 Hz), 7.28 (1H, d, J=3.2 Hz), 7.20 (1H, t, J=8.0 Hz), 6.63 (1H, d, J=3.6 Hz), 6.33 (1H, m), 4.76 (2H, m), 3.85 (3H, s) ppm.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The title compound was prepared in a similar procedure as described in Example (R)-3-((1-amino-3-methyl-1-oxobutan-2-yl)amino)-5-((1-methyl-1H-indol-4-yl)amino)-1,2,4-triazine-6-carboxamide. Here though, 5-(aminomethyl)pyrrolidin-2-one was utilized instead of (R)-2-amino-3-methylbutanamide. MS found for C18H20N8O2 as (M+H)+ 381.3. UV: λ=219, 239, 292 nm. Proton NMR: (CD3OD) δ 7.90 (1H, d, J=8.0 Hz), 7.36-7.22 (3H, m), 6.60 (1H, dd, J=0.8 Hz, 2.8 Hz), 3.98 (1H, m), 3.84 (3H, s), 3.62-3.51 (2H, m), 2.40, −2.20 (3H, m), 1.90 (1H, m) ppm.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The title compound was prepared in a similar procedure as described in Example (R)-3-((1-amino-3-methyl-1-oxobutan-2-yl)amino)-5-((1-methyl-1H-indol-4-yl)amino)-1,2,4-triazine-6-carboxamide. Here though, 5-(aminomethyl)pyrrolidin-2-one was utilized instead of (R)-2-amino-3-methylbutanamide. MS found for C18H20N8O2 as (M+H)+ 381.3. UV: λ=219, 239, 292 nm. Proton NMR: (CD3OD) δ 7.90 (1H, d, J=8.0 Hz), 7.36-7.22 (3H, m), 6.60 (1H, dd, J=0.8 Hz, 2.8 Hz), 3.98 (1H, m), 3.84 (3H, s), 3.62-3.51 (2H, m), 2.40, −2.20 (3H, m), 1.90 (1H, m) ppm.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of D-valinamide (1.76 g, 14.7 mmol) in acetonitrile (30 mL) was slowly added 1,3-propanesultone (1.75 g, 14.4 mmol). The solution was stirred at reflux for 2 hours. The reaction mixture was cooled to room temperature. The solid was collected by filtration, washed with acetonitrile (2×25 mL). The solid product was dissolved in water (75 mL). Dowex Marathon C resin (strongly acidic) was added to the solution. The suspension was stirred for 15 minutes before the resin was removed by filtration. The filtrate was evaporated under reduced pressure. The solid material was suspended in acetone (50 mL), filtered and dried in vacuo, affording the title compound (1.57 g, 51%). 1H NMR (D2O, 500 MHz) δ ppm 3.80 (m, 1H), 3.19 (m, 2H), 3.00 (m, 2H), 2.25 (m, 1H), 2.16 (m, 2H), 1.08 (d, 3H, J=6.8 Hz), 1.02 (d, 3H, J=6.8 Hz). 13C (D2O, 125 MHz) δ ppm 169.94, 65.86, 48.10, 46.27, 29.54, 21.23, 17.99, 17.02. [α]D=−12.4° (c=0.0037 in water), ES-MS 237 (M−1). at reflux for 2 hours The solid was collected by filtration washed with acetonitrile (2×25 mL) The solid product was dissolved in water (75 mL) Dowex Marathon C resin (strongly acidic) was added to the solution The suspension was stirred for 15 minutes before the resin was removed by filtration The filtrate was evaporated under reduced pressure filtered dried in vacuo

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The title compound was prepared in a similar procedure as described in Example (R)-3-((1-amino-3-methyl-1-oxobutan-2-yl)amino)-5-((1-methyl-1H-indol-4-yl)amino)-1,2,4-triazine-6-carboxamide. Here though, 5-(aminomethyl)pyrrolidin-2-one was utilized instead of (R)-2-amino-3-methylbutanamide. MS found for C18H20N8O2 as (M+H)+ 381.3. UV: λ=219, 239, 292 nm. Proton NMR: (CD3OD) δ 7.90 (1H, d, J=8.0 Hz), 7.36-7.22 (3H, m), 6.60 (1H, dd, J=0.8 Hz, 2.8 Hz), 3.98 (1H, m), 3.84 (3H, s), 3.62-3.51 (2H, m), 2.40, −2.20 (3H, m), 1.90 (1H, m) ppm.

Conditions: temp:5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In an inert thermostable reactor provided with a mechanical stirrer, 94.25 g of Ac-D-Lys(Z)-D-Pro-OH (XI) (224.7 mmol) are introduced followed by 470 ml of DMF. 32.58 g of HCl. H-D-Val-NH2 (V) (213.5 mmol, 0.95 eq) and 85.22 g of HBTU (1 eq) are then added. The medium is cooled down to 5° C., and 96.6 ml of ethyldiisopropylamine (2.5 eq) are added dropwise within 15 minutes. This is allowed to reach 0° C. again and after 1.30 to 2 hours, a strong crystallization could be observed. The reaction completion is CCM controlled. The reaction medium is then poured onto 2350 ml of AcOEt, stirred for 15 minutes, filtered and washed successively with 470 ml of AcOEt and 470 ml of diisopropyl ether. The derivate (XII) is vacuum dried at 25° C. This way, 107.2 g (92%) pf Ac-D-Lys(Z)-D-Pro-D-Val-NH2 are obtained. In an inert thermostable reactor provided with a mechanical stirrer to reach 0° C. a strong crystallization The reaction medium is then poured onto 2350 ml of AcOEt filtered washed successively with 470 ml of AcOEt and 470 ml of diisopropyl ether dried at 25° C

Conditions: temp:5.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In an inert thermostable reactor provided with a mechanical stirrer, 94.25 g of Ac-D-Lys(Z)-D-Pro-OH (XI) (224.7 mmol) are introduced followed by 470 ml of DMF. 32.58 g of HCl. H-D-Val-NH2 (V) (213.5 mmol, 0.95 eq) and 85.22 g of HBTU (1 eq) are then added. The medium is cooled down to 5° C., and 96.6 ml of ethyldiisopropylamine (2.5 eq) are added dropwise within 15 minutes. This is allowed to reach 0° C. again and after 1.30 to 2 hours, a strong crystallization could be observed. The reaction completion is CCM controlled. The reaction medium is then poured onto 2350 ml of AcOEt, stirred for 15 minutes, filtered and washed successively with 470 ml of AcOEt and 470 ml of diisopropyl ether. The derivate (XII) is vacuum dried at 25° C. This way, 107.2 g (92%) pf Ac-D-Lys(Z)-D-Pro-D-Val-NH2 are obtained. In an inert thermostable reactor provided with a mechanical stirrer to reach 0° C. a strong crystallization The reaction medium is then poured onto 2350 ml of AcOEt filtered washed successively with 470 ml of AcOEt and 470 ml of diisopropyl ether dried at 25° C

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of (R)-2-amino-3-methyl-butyramide (50 mg), 2,4,5-trichloropyrimidine (67 mg) and K2CO3 (116 mg) in DMF (3 mL) was stirred at room temperature for 5 hr. The reaction mixture was diluted with DCM and washed with brine three times. The organic layer was dried with sodium sulfate and concentrated. The residue was purified by silica gel chromatography to provide 60 mg of (R)-2-(2,5-dichloro-pyrimidin-4-ylamino)-3-methyl-butyramide: 1H NMR (300 MHz, CDCl3) 8.2 (s, 1H), 6.2 (bs, 1H), 5.8 (bs, 1H), 5.6 (bs, 1H), 4.6 (dd, 1H), 2.4 (m, 1H), 1.2 (d, 6H). MS (m/e) 263 (M+1). washed with brine three times The organic layer was dried with sodium sulfate concentrated The residue was purified by silica gel chromatography

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of (R)-2-amino-3-methyl-butyramide (50 mg), 2,4,5-trichloropyrimidine (67 mg) and K2CO3 (116 mg) in DMF (3 mL) was stirred at room temperature for 5 hr. The reaction mixture was diluted with DCM and washed with brine three times. The organic layer was dried with sodium sulfate and concentrated. The residue was purified by silica gel chromatography to provide 60 mg of (R)-2-(2,5-dichloro-pyrimidin-4-ylamino)-3-methyl-butyramide: 1H NMR (300 MHz, CDCl3) 8.2 (s, 1H), 6.2 (bs, 1H), 5.8 (bs, 1H), 5.6 (bs, 1H), 4.6 (dd, 1H), 2.4 (m, 1H), 1.2 (d, 6H). MS (m/e) 263 (M+1). washed with brine three times The organic layer was dried with sodium sulfate concentrated The residue was purified by silica gel chromatography